Hematologic Malignancy Patients Research Articles

An Asian multi-regional registry study of rare cancers: The MASTER KEY ASIA and MASTER KEY Japan projects.

e15052 Background: The importance of biomarker-based treatment and individual therapeutic strategies can be even more substantial in rare cancers, which confront particular difficulties, such as delayed or inaccurate diagnosis, lack of clinical knowledge, and less interest in the development of innovative treatment. However, large-scale studies point to the challenge of drug development disparities between populations, demonstrating the need to better understand the diverse genomic and clinical characteristics. Methods: The present study aimed to characterize rare tumors and recognize the genomic and clinical diversity of Asian and Japanese cohorts. The study included patients with histologically diagnosed rare cancer, defined as those with an annual incidence of < 6/100,000 people. Patients’ clinical data as well as biomarker data were collected. Biomarker analysis included next-generation sequencing (NGS), immunohistochemical staining, fluorescent in situ hybridization (FISH), or single gene testing. Tumor Mutational Burden (TMB) was evaluated through NGS, and was defined as TMB-High (≥10 per Mb) or TMB-Low ( < 10 per Mb). Results: For the Japanese cohort, a total of 2797 solid rare cancer (MKJ solid) and 260 hematological malignancy (MKJ Hem) patients were enrolled in the study between May 2017 and Dec 2022. For the Asian cohort (MKA solid), a total of 226 solid rare cancer patients were enrolled between Nov 2021 to Dec 2022, from countries of Malaysia (n = 175), Philippines (n = 27), Korea (n = 13), and Taiwan (n = 11). From the MKA, 185 patients received a complete diagnosis, of which 92 had genetic biomarker analysis. MKJ solid had 2702 patients diagnosed, among which 1460 were genetically analyzed. The median age for solid rare cancer patients was 55.3 years for MKJ solid, and 50.6 years for MKA solid. Soft tissue sarcomas and CNS/Brain rare cancers were the most frequent types of rare cancers in the recruited patients of MKJ (n = 611 and 395, respectively), but Head and Neck cancers were less common in the Japanese cohort compared to other Asia countries (MKJ = 8%, MKA = 18%). TP53 is a common biomarker in solid cancer alterations, and it was indeed the most recurrent alteration in both solid cancer cohorts, altered in 50% of the MKA solid cohort and in 66% of the MKJ solid cohort. The proportion of TMB-high was 12% and 8% in the MKA solid and MKJ solid cohorts, respectively. Conclusions: The clinical and genomic characteristics of rare cancers from an Asian multi-regional registry study were identified. These cohorts provide a novel way to understand the population-based dimension of rare cancers and, therefore, the need for detailed molecular investigations to enhance clinical oncology practice.

Impact of Infection Patterns on the Outcomes of Patients with Hematological Malignancies in Southwest China: A 10-Year Retrospective Case-Control Study.

This study aimed to assess the effect of infection patterns on the outcomes of patients with hematological malignancies (HM) and to identify the determinants of in-hospital mortality. A case-control study was retrospectively conducted in a tertiary teaching hospital in Chongqing, Southwest China from 2011 to 2020. Clinical characteristics, microbial findings, and outcomes of HM patients with infections were retrieved from the hospital information system. Chi-square or Fisher's exact test was adopted to test the significance of mortality rate. Kaplan-Meier survival analysis and Log rank test were applied to evaluate and compare the 30-day survival rates of those groups. Binary logistic regression, Cox proportional hazards regression, and receiver operating characteristic curves were used to investigate the determinants of in-hospital mortality. Of 1,570 enrolled participants, 43.63% suffered from acute myeloid leukemia, 69.62% received chemotherapy, and 25.73% had hematopoietic stem cell transplantation (HSCT). Microbial infection was documented in 83.38% of participants. Co-infection and septic shock were reported in 32.87% and 5.67% of participants, respectively. Patients with septic shock suffered a significantly lower 30-day survival rate, while those with distinct types of pathogens or co-infections had a comparable 30-day survival rate. The all-cause in-hospital mortality was 7.01% and higher mortality rate was observed in patients with allo-HSCT (7.20%), co-infection (9.88%), and septic shock (33.71%). Cox proportional hazards regression illustrated that elderly age, septic shock, and elevated procalcitonin (PCT) were independent predictors of in-hospital mortality. A PCT cut-off value of 0.24 ng/mL predicted in-hospital mortality with a sensitivity of 77.45% and a specificity of 59.80% (95% CI = 0.684-0.779, P<0.0001). Distinct infectious patterns of HM inpatients were previously unreported in Southwest China. It was the severity of infection, not co-infection, source of infection, or type of causative pathogen that positively related to poor outcome. PCT guided early recognition and treatment of septic shock were advocated.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Purpose/Objectives: During COVID19, shorter radiation therapy (RT) courses were considered to minimize patient exposure, ensure staff safety, and conserve healthcare resources. Due to concerns with the safety of systemic therapy, RT demands were also increased. In response, guidelines were published by the International Lymphoma Radiation Oncology Group (ILROG) to guide the treatment of hematologic malignancies patients with hypofractionated radiation therapy (hRT) regimens. These guidelines suggested hRT dose/fractionation schemes based on the known radiosensitivity of various hematologic malignancies with consideration of the biologically equivalent doses in the hRT setting. However, the outcomes for these dose/fractionation regimens in terms of efficacy and toxicity are unknown. Materials/Methods: In collaboration with ILROG, we performed a retrospective multinational, multicenter study. We included any patient treated from 1/1/2020 to 8/31/2020 with hRT given according to the published ILROG guidelines or hRT given at >3 Gy per fraction. We abstracted patient and treatment data from the respective institutional databases. CTCAE v5.0 was used to grade toxicity. Results: We included 237 patients from 8 different institutions treated with 282 RT courses. Patient and treatment details are reported in Table 1. Median RT dose was 12 Gy (range 4–39) in a median of 3 fractions (range 1–13). Median follow up was 181 days, with 174 patients (73%) alive at last follow up. Response within the RT field was assessed in 228 sites: complete response (CR) (n = 143, 63%); partial response (PR) (n = 59, 26%); stable disease (SD) (n = 15, 7%); and progressive disease (PD) (n = 11, 5%). Maximal toxicities reported were Grade 1 (n = 45), Grade 2 (n = 24), Grade 3 (n = 4) and Grade 4 (n = 1). Grade 3 toxicities occurred with the following treatment regimens: 12 Gy in 3 fx to extremity (dermatitis, given concurrent with methotrexate); 30 Gy in 6 fx to extremity (dermatitis); 20 Gy in 5 fx to pelvis (pain); 25 Gy in 5 fx to abdomen (pain). One grade 4 toxicity occurred with 12 Gy in 3 fx to the CNS (hematologic toxicity). Conclusions: Treatment of hematologic malignancies patients with hRT was generally well tolerated with few unexpected toxicities. Evaluation of efficacy is limited by patient and treatment heterogeneity but appears to be reasonable. These data can provide guidance for emergency situations requiring minimization of patient and staff exposure. Perhaps more importantly, hRT could be considered even in routine settings to spare patients time on treatment, especially for certain patient subgroups. Keyword: Radiation Therapy Conflicts of interests pertinent to the abstract. U. Ricardi Consultant or advisory role: Advisory Board member and Speaker Honoraria: Astra Zeneca Research funding: Institutional Research Cooperation: Accuray, BrainLab L. Specht Consultant or advisory role: Takeda, Kyowa Kirin, MSD Honoraria: Takeda Research funding: Varian, ViewRay, Danish Cancer Society

Outcomes of hematological malignancy patients who underwent myeloablative haploidentical transplant with PTCy and ATG.

e19057 Background: Haplo-HCT is a potentially curative intervention for hematological malignancies. A number of transplant platforms are used by different groups. We adopted a myeloablative conditioning (MAC) protocol, BM graft with post-transplant cyclophosphamide (PTCy) for GvHD prophylaxis as our program cares for young patients with hematologic malignancies. High grades GvHD were noticed, antithymocyte globulin (ATG) 2mg/kg was added to the platform. During COVID19 outbreak PBSCT was used as a graft source. Methods: Retrospective review of patients who underwent myeloablative Haplo-HCT for malignant hematologic disorders using ATG and PTCy for GvHD prophylaxis. Patient characteristics were summarized using frequencies for categorical variables and medians with ranges for continuous variables. Probabilities of overall survival (OS), relapsed-free survival (RFS) were summarized using Kaplan-Meier estimator with variance estimated using Greenwood’s formula. Survival curves were compared using the log-rank test. Probabilities of aGvHD, cGvHD, and extensive cGvHD were calculated using cumulative incidence function (CIF) taking into consideration DLI and death without GvHD. Probabilities of and relapse and non-relapsed mortality (NRM) were calculated using CIF taking into consideration death without GvHD and NRM and relapse as competing risks, respectively. Results: 60 patients were reviewed, 32 (53%) were males and 28 (47%) females. 57% had AML and 23% had ALL. Other diagnoses included CML, MDS, APL and BPDCN. 73% received BM graft and 27% PBSCT graft. The conditioning was myeloablative in the form of Thio/Bu/Flu (68%) for myeloid malignancies and Flu/TBI 1000 cGy (27%) for lymphoid malignancies. Most donors were males (57%) siblings (60%), with more than 50% HLA matching (58%), and no ABO mismatch (70%). Disease risk index (DRI) was intermediate in most cases (38%) followed by high (32%). At 5 years, the OS was 59% (95% CI: 46%-73%), RFS was 49% (95% CI: 34%-63%). 42% patients developed grade 2-4 aGvHD and 15% of patients developed extensive cGvHD. OS of patients &gt; 50 years old was 21% (95% CI: 0%-56%). There were no cases of primary GF but 1 patient developed secondary GF. 17 patients developed HCYST (28%) and 17 (28%) needed ICU admission. Most patients (88%) developed CMV reactivation, and 2 patients developed VOD. We analyzed DRI, donor age, TBI vs. non-TBI, BM vs. PBSCT, donor relation, level of HLA matching, ABO mismatch, female vs. male donor, effects on OS, RFS and GvHD. None of these variables had significant association with OS. Higher DRI was associated with higher relapse (P0.04). Donor recipient sex mismatch and donor age were associated with cGvHD. Conclusions: Myeloablative Haplo-HCT for hematological malignancies with PTCy and ATG is safe and associated with acceptable OS, RFS and low rate of extensive cGvHD. Older patients require adjustment due to risk of higher NRM.

CD317 maintains proteostasis and cell survival in response to proteasome inhibitors by targeting calnexin for RACK1-mediated autophagic degradation

Unbalanced protein homeostasis (proteostasis) networks are frequently linked to tumorigenesis, making cancer cells more susceptible to treatments that target proteostasis regulators. Proteasome inhibition is the first licensed proteostasis-targeting therapeutic strategy, and has been proven effective in hematological malignancy patients. However, drug resistance almost inevitably develops, pressing for a better understanding of the mechanisms that preserve proteostasis in tumor cells. Here we report that CD317, a tumor-targeting antigen with a unique topology, was upregulated in hematological malignancies and preserved proteostasis and cell viability in response to proteasome inhibitors (PIs). Knocking down CD317 lowered Ca2+ levels in the endoplasmic reticulum (ER), promoting PIs-induced proteostasis failure and cell death. Mechanistically, CD317 interacted with calnexin (CNX), an ER chaperone protein that limits calcium refilling via the Ca2+ pump SERCA, thereby subjecting CNX to RACK1-mediated autophagic degradation. As a result, CD317 decreased the level of CNX protein, coordinating Ca2+ uptake and thus favoring protein folding and quality control in the ER lumen. Our findings reveal a previously unrecognized role of CD317 in proteostasis control and imply that CD317 could be a promising target for resolving PIs resistance in the clinic.

A Case Report of Lung Transplantation After Hematopoietic Stem Cell Transplantation and Literature Review

Pulmonary complications may occur after hematopoietic stem cell transplantation for hematologic malignancies. Lung transplantation is the only treatment option for end-stage lung failure. We presented a case of acute myeloid leukemia who received a hematopoietic stem cell transplantation and underwent bilateral lung transplantation with end-stage usual interstitial pneumonia and chronic obstructive lung disease. This case showed that lung transplantation could be successfully applied in properly selected hematologic malignancy patients with long disease-free survival, like lung transplantations performed for other indications.

Estimating the prevalence of pediatric hematological malignancies in Al-Madinah Al-Munawwarah, Saudi Arabia.

To provide an updated estimate to the prevalence of pediatric hematological malignancies (HMs) in the Al-Madinah Al-Munawwara, Saudi Arabia. This is a retrospective study that was carried out between 2016 and 2022. The study population was comprised of 171 children under 16 who had been diagnosed with HMs. The data was compiled from King Salman Medical City's Maternity and Children's Hospital, Al-Madinah Al-Munawwarah, Saudi Arabia. Among the 171 HM patients (64% males and 36% females), 13 subtypes were identified, with B-cell acute lymphoblastic leukemia having the highest incidence (70.3%). Acute myelomonocytic leukemia (8.7%), T-cell acute lymphoblastic leukemia (4.7%), and acute promyelocytic leukemia (3.5%) were the next most common types of HMs. Other rare cases were also found. Prevalence rate can be utilized to monitor the progression of disease incidence. Here, HMs demonstrated a pattern of increasing incidence in males over a 7-year period, with a higher rate in early childhood. There were 13 types of HMs diagnosed, with B-acute lymphocytic leukemia having the highest incidence. Although juvenile cancer is rare, it is nonetheless a significant cause of mortality in children. A successful prognosis requires prompt and accurate diagnosis and treatment.

Characterization of post-vaccination SARS-CoV-2 T cell subtypes in patients with different hematologic malignancies and treatments.

To evaluate the benefits of SARS-CoV-2 vaccination in cancer patients it is relevant to understand the adaptive immune response elicited after vaccination. Patients affected by hematologic malignancies are frequently immune-compromised and show a decreased seroconversion rate compared to other cancer patients or controls. Therefore, vaccine-induced cellular immune responses in these patients might have an important protective role and need a detailed evaluation. Certain T cell subtypes (CD4, CD8, Tfh, γδT), including cell functionality as indicated by cytokine secretion (IFN, TNF) and expression of activation markers (CD69, CD154) were assessed via multi-parameter flow cytometry in hematologic malignancy patients (N=12) and healthy controls (N=12) after a second SARS-CoV-2 vaccine dose. The PBMC of post-vaccination samples were stimulated with a spike-peptide pool (S-Peptides) of SARS-CoV-2, with CD3/CD28, with a pool of peptides from the cytomegalovirus, Epstein-Barr virus and influenza A virus (CEF-Peptides) or left unstimulated. Furthermore, the concentration of spike-specific antibodies has been analyzed in patients. Our results indicate that hematologic malignancy patients developed a robust cellular immune response to SARS-CoV-2 vaccination comparable to that of healthy controls, and for certain T cell subtypes even higher. The most reactive T cells to SARS-CoV-2 spike peptides belonged to the CD4 and Tfh cell compartment, being median (IQR), 3.39 (1.41-5.92) and 2.12 (0.55-4.14) as a percentage of IFN- and TNF-producing Tfh cells in patients. In this regard, the immunomodulatory treatment of patients before the vaccination period seems important as it was strongly associated with a higher percentage of activated CD4 and Tfh cells. SARS-CoV-2- and CEF-specific T cell responses significantly correlated with each other. Compared to lymphoma patients, myeloma patients had an increased percentage of SARS-CoV-2-specific Tfh cells. T-SNE analysis revealed higher frequencies of γδT cells in patients compared to controls, especially in myeloma patients. In general, after vaccination, SARS-CoV-2-specific T cells were also detectable in patients without seroconversion. Hematologic malignancy patients are capable of developing a SARS-CoV-2-specific CD4 and Tfh cellular immune response after vaccination, and certain immunomodulatory therapies in the period before vaccination might increase the antigen-specific immune response. A proper response to recall antigens (e.g., CEF-Peptides) reflects immune cellular functionality and might be predictive for generating a newly induced antigen-specific immune response as is expected after SARS-CoV-2 vaccination.

COVID-19 infection in patients with haematological malignancies: A single-centre survey in the latest Omicron wave in China.

As the COVID-19 variant Omicron surge in Beijing, China, a better understanding of risk factors for adverse outcomes may improve clinical management in patients with haematological malignancies (HM) diagnosed with COVID-19. The study sample includes 412 cases, mainly represented by acute leukaemia, chronic myeloid leukaemia (CML), plasma cell disorders and lymphoma and chronic lymphocytic leukaemia. COVID-19 pneumonia was observed in 10.4% (43/412) of patients, and severe/critical illness was observed in 5.3% (22/412). Among the 86 cases with advanced malignancies, 17.6% (12/86) of patients developed severe/critical COVID-19, which was significantly higher than reported in patients with stable malignancies (9/326, 2.70%, p < 0.001). Similarly, the advanced malignancy cohort had a higher mortality rate (9/86, 10.5% vs. 0/326, 0%, p < 0.001) and a poor 30-day overall survival (OS) compared with the stable malignancy cohort (74.2% vs. 100.0%, p < 0.0001). Overall, nine patients (2.2%) died. The primary cause of death was progressive HM in four patients and a combination of both COVID-19 and HM in five patients. In the multivariable analysis, over 65 years of age, comorbidities and advanced malignancy were correlated with severe/critical COVID-19 in HM patients. This study sheds light on the poor outcomes among COVID-19 HM patients with the leading cause of advanced malignancy.

Use of monoclonal antibody therapy in hematologic patients with mild‐to‐moderate COVID‐19: A retrospective single‐center experience

In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n= 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n= 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n= 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n= 0/26 and 36% n= 4/11, respectively; p< 0.01). This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients.

Metabolic challenges and interventions in CAR T cell therapy.

Chimeric antigen receptor (CAR) T cells have achieved true clinical success in treating hematological malignancy patients, laying the foundation of CAR T cells as a new pillar of cancer therapy. Although these promising effects have generated strong interest in expanding the treatment of CAR T cells to solid tumors, reproducible demonstration of clinical efficacy in the setting of solid tumors has remained challenging to date. Here, we review how metabolic stress and signaling in the tumor microenvironment, including intrinsic determinants of response to CAR T cell therapy and extrinsic obstacles, restrict the efficacy of CAR T cell therapy in cancer treatment. In addition, we discuss the use of novel approaches to target and rewire metabolic programming for CAR T cell manufacturing. Last, we summarize strategies that aim to improve the metabolic adaptability of CAR T cells to enhance their potency in mounting antitumor responses and survival within the tumor microenvironment.

Bloodstream infections due to Gram-negative bacteria in patients with hematologic malignancies: updated epidemiology and risk factors for multidrug-resistant strains in an Italian perspective survey

Bloodstream infections (BSI) caused by Gram-negative bacteria (GNB) in patients with hematological malignancies (HM) have been associated with high mortality rates, particularly with infections caused by antibiotic-resistant strains.A multicenter cohort study including all consecutive episodes of GNB BSI in HM patients was conducted to update the epidemiology and antibiotic resistance patterns (compared to our previous survey conducted between 2009 and 2012) and investigate risk factors for GNB BSI due to multidrug-resistant (MDR) isolates.A total of 834 GNB were recovered in 811 BSI episodes from January 2016 to December 2018. Compared to the previous survey, there was a significant reduction in use of fluoroquinolone prophylaxis and a significant recovery in susceptibility rates to ciprofloxacin among Pseudomonas aeruginosa, Escherichia coli and Enterobacter cloacae isolates. In addition, there was a shift to a significantly increased susceptibility of P. aeruginosa isolates to ceftazidime, meropenem, and gentamicin. A total of 256/834 (30.7%) isolates were MDR. In multivariable analysis, MDR bacteria culture-positive surveillance rectal swabs, previous therapy with aminoglycosides and carbapenems, fluoroquinolone prophylaxis, and time at risk were independently associated with MDR GNB BSI.In conclusion, despite the persistence of a high prevalence of MDR GNB, there was a shift to a reduced use of fluoroquinolone prophylaxis and increased rates of susceptibility to fluoroquinolones in almost all isolates and to almost all antibiotics tested among P. aeruginosa isolates, compared to our previous survey. Fluoroquinolone prophylaxis and previous rectal colonization by MDR bacteria were independent risk factors for MDR GNB BSI in the present study.

Contribution of the Oral and Gastrointestinal Microbiomes to Bloodstream Infections in Leukemia Patients.

Bloodstream infections (BSIs) pose a significant mortality risk for acute myeloid leukemia (AML) patients. It has been previously reported that intestinal domination (>30% relative abundance [RA] attributed to a single taxon) with the infecting taxa often precedes BSI in stem cell transplant patients. Using 16S rRNA amplicon sequencing, we analyzed oral and stool samples from 63 AML patients with BSIs to determine the correlation between the infectious agent and microbiome composition. Whole-genome sequencing and antimicrobial susceptibilities were performed on all BSI isolates. Species-level detection of the infectious agent and presence of antibiotic resistance determinants in the stool (blaCTX-M-15, blaCTX-M-14, cfrA, and vanA) were confirmed via digital droplet PCR (ddPCR). Individuals with Escherichia coli (stool P < 0.001), Pseudomonas aeruginosa (oral P = 0.004, stool P < 0.001), and viridans group streptococci (VGS) (oral P = 0.001) bacteremia had a significantly higher relative abundance of those respective genera than other BSI patients, which appeared to be site specific. Although 78% of patients showed presence of the infectious genera in the stool and/or saliva, only 7 exhibited microbiome domination. ddPCR confirmed species specificity of the 16S data and detected the antibiotic resistance determinants found in the BSI isolates within concurrent stools. Although gastrointestinal (GI) domination by an infecting organism was not present at the time of most BSIs in AML, the pathogens, along with AMR elements, were detectable in the majority of patients. Thus, rapid genetic assessment of oral and stool samples for the presence of potential pathogens and AMR determinants might inform personalized therapeutic approaches in immunocompromised patients with suspected infection. IMPORTANCE A major cause of mortality in hematologic malignancy patients is BSI. Previous studies have demonstrated that bacterial translocation from the GI microbiome is a major source of BSIs and is often preceded by increased levels of the infectious taxa in the GI (>30% abundance by 16S rRNA sequencing). In this study, we sought to better understand how domination and abundance levels of the oral and gut microbiome relate to bacteremia occurrence in acute myeloid leukemia patients. We conclude that analyses of both oral and stool samples can help identify BSI and antimicrobial resistance determinants, thus potentially improving the timing and tailoring of antibiotic treatment strategies for high-risk patients.

Abstract 3010: Epigenetic age acceleration in older adults with hematologic malignancies

Abstract Background: Older adults with hematologic malignancy (HM) are a growing demographic with heterogenous health needs. Chronologic age, performance status and comorbidities impact the selection and intensity of treatments but may not accurately predict treatment toxicity or resiliency. Here, we conducted longitudinal measures of clinical frailty and epigenetic age to explore the relationships between physiologic aging and fitness. Methods: Newly diagnosed patients &amp;gt;60 years with HM were enrolled in a prospective longitudinal study with biomarkers procured at baseline (pre-therapy) and end-of-study (EOS). EOS was defined as the earliest of the following events: progression, transplant, or 1-year from baseline. Peripheral blood was collected, CD3+ T-cells isolated, and DNA extracted using a column-based commercial nucleic acid kit. Peripheral blood T lymphocytes samples were also procured from healthy controls using identical methods. PBTL was extracted, bisulfite converted, and methylation was quantified using the Illumina 850K EPIC methylation array at the TruDiagnostic core laboratory. Raw data was processed using the minfi pipeline, followed by normalization, batch correction, and KNN-based imputation using the GMQN and impute R packages. Principal-component (PC) PhenoAge measures were calculated using the processed methylation values. Measured clinical phenotypes of fitness included ECOG, independent activities of daily living, physical health scores, comorbidities, cognition (BOMC) and objective measures of function (SPPB). Results: 94 patients with HM (acute leukemia n=35, lymphoma n=23, CLL = 6, plasma cell n=30) with PBTL and clinical fitness data were evaluated. The median chronologic age was 70.55 years (range 28.71 yrs, IQR = 10.84). mPhenoAge was higher in patients with HM (Median = 49.59 yrs, Range = 71.245, IQR = 12.52) than healthy donors (Median = 30.46; Range = 75.58, IQR = 32.83). Patients with acute leukemia had the highest mPhenoAge (57.10 yrs, Range = 61.97, IQR = 30.03; p=3e-04). mPhenoage was lower in patients with ECOG 0 vs ECOG 1 (p=0.011). Patients with Acute leukemia also showed a decrease in mPhenoage at EOS (p=0.034), which was not seen in other HMs. Patient IADLs (p=0.032) and comorbidities (p=0.009) were positively correlated with Epigenetic Age Acceleration (EAA). Patient cognitive score (p=0.053) negatively correlated with EAA. mPhenoAge decreased more in patients who received hypomethylating therapies than those who received high-dose multi-drug chemotherapy, low-dose multi-drug chemotherapy or targeted agents. Conclusions: Physiologic age, as measured by PBTL mPhenoAge, is increased among older adults with HMs relative to healthy controls. PBTL mPhenoAge is highest among HM patients with acute leukemia and changes are associated with clinical phenotypes. PBTL mPhenoAGE decreased with hypomethylating agents in patients with acute leukemia. Citation Format: Ashley E. Rosko, Kaitlyn Dvorak, Jennifer Woyach, Varun Dwaraka, Ryan Smith, Ryann Finlayson, Alice Mims, Christin Burd. Epigenetic age acceleration in older adults with hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3010.

The Risk and Survival Analysis of Multiple Malignancies in Hematologic Malignancy Patients: A Single Chinese Center Retrospective Study, 2009 through 2017

To explore the risk and location of multiple malignancies in patients with hematologic malignancies who were followed up for 9 years in Jiangsu Province Hospital and to evaluate the impact of the second primary malignancy on survival of patients. The incidence and survival of multiple malignancies in 7 921 patients with hematologic malignancies from 2009 to 2017 were analyzed retrospectively. A total of 180 (2.3%, 180/7 921) patients developed second malignancy, of whom 58 patients were diagnosed with hematologic malignancies as the first primary malignancy, and 98 patients developed hematologic malignancies as second primary malignancy, and the other 24 cases were diagnosed with the second malignancy within 6 months after the first primary malignancy was diagnosed, which was difined as multiple malignancies occurring simultaneously. In 180 patients, 18 cases developed two hematologic malignancies successively, and 11 patients developed more than 3 primary cancers (among them, 2 female patients were diagnosed with 4 primary cancers). Patients with lymphoma and multiple myeloma (MM) as the second primary malignancy had poorer survival than patients with lymphoma and MM as the first primary malignancy. Patients with chronic myeloid leukemia as the second primary malignancy were also associated with inferior overall survival. In this study, 2.3% of hematologic malignancy patients had multiple mali-gnancies, lymphoma and MM as the second primary malignancy had poor survival.

Epidemiology and Factors Associated with Treatment Success of Invasive Fungal Infections Among Newly Hematologic Malignancy Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant in Thailand.

Invasive fungal infection (IFI) causes disability/death in patients with hematologic malignancy (HM) receiving chemotherapy or hematopoietic stem cell transplant (HSCT). There is limited epidemiological data, treatment outcomes, and factors associated with IFI treatment success in Thailand. This study aimed to identify factors associated with IFI treatment success among new HM patients receiving chemotherapy or HSCT, determine IFI incidence among HM patients receiving chemotherapy or HSCT, and the IFI incidence of a breakthrough in patients receiving primary antifungal prophylaxis, and identify antifungal drugs susceptibility. This study reviewed the charts of patients aged ≥ 15 years with newly HM who received chemotherapy or HSCT between January 2016 and June 2021 at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. The 2020 EORTC/MSG criteria were used to diagnose IFI. IFI treatment success factors were evaluated using logistic regression. Ninety-two patients with 107 episodes of IFI met the inclusion criteria. IFI incidence on proven and probable cases among newly HM patients receiving chemotherapy or HSCT was 7%. Most infections (38.3%) occurred during the induction-phase chemotherapy. Aspergillosis (35.5%) was the commonest IFI, followed by candidiasis (11.2%), Pneumocystis jirovecii pneumonia (8.4%), mucormycosis (3.7%), and others, respectively. The 12-week IFI treatment success rate was 67.3%. It was associated with age < 60 years, absence of coinfection, and the receipt of appropriate empirical therapy on the first day of IFI diagnosis. The incidence of breakthrough IFI from proven and probable cases in patients receiving primary antifungal prophylaxis was 6.1%. Most fungal pathogen isolates were still highly susceptible to antifungal drugs. The IFI treatment success in patients with HM or HSCT in our study was high. Close monitoring of coinfected patients aged ≥ 60 is recommended. Appropriate antifungal drugs are essential for clinical outcomes.

Rhinovirus, When Is It More Than Just a Cold? Rhinovirus as a Cause of Organizing Pneumonia in Two Patients With Hematological Cancer

Abstract Human rhinoviruses are pathogens that cause significant morbidity and economic strain from upper respiratory infections. Rhinovirus has also been associated with exacerbations of chronic lung disease. Less understood is the role of rhinovirus in organizing pneumonia (OP). Organizing pneumonia is a certain lung pattern of injury that occurs after injury to the pulmonary parenchyma, with infection being the most studied etiology. It typically presents with similar symptoms to pneumonia, and patients are often treated with antibiotics to lack of improvement. However, OP is more subacute in presentation, and the treatment, systemic glucocorticoids, differs from bacterial pneumonia. Recognition of rhinovirus as a significant pathogen in immunocompromised patients is important because it tends to cause more severe disease in this group. Here, we present a case series of 2 hematological malignancy patients with a long-standing rhinovirus infection and lung disease unresponsive to antibiotics, later found on biopsy to be OP. Both patients survived the infection, and both patients had documented rhinovirus shedding for greater than 9 months. Both patients had lymphoma and were being actively treated with a monoclonal antibody that targeted cluster of differentiation 20. Both patients reported fever and dyspnea. Both patients had multiple superimposed bacterial infections, with both patients eventually developing Pseudomonas aeruginosa pneumonia. In the immunocompromised, rhinovirus may cause morbidity through a primary infection, a secondary bacterial infection, or OP. Novel treatment strategies and increased awareness are needed not only for rhinovirus-induced OP but also for rhinovirus as an important pathogen in immunocompromised patients.

Direct oral anticoagulants in patients with venous thromboembolism and hematological malignancies

Data are needed on direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) in hematological malignancies (HM). Retrospective studies to date lacked a control group and did not focus on patients with VTE. Out aim was toassess the incidence of VTE recurrence and bleeding in HM patients treated with low molecular weight heparin (LMWH) or DOACs for acute VTE. This is a retrospective cohort study including patients with active HM and newly-diagnosed VTE, indexed on the first day of anticoagulation and followed for 12months. The outcome was a composite of recurrent VTE, major bleeding or clinically relevant non-major bleeding. Cumulative incidence [95% confidence interval (CI)] was calculated for each anticoagulation group (LMWH, DOAC) and hazard ratios (HR) were calculated using cox-proportional hazards model, with death as a competing risk. 143 HM patients treated with LMWH (96) or DOACs (47) for acute VTE were included. The most common HM types were lymphoma in 83 (58%) and plasma cell dyscrasia in 32 (22.3%). The 12-month cumulative incidence of the composite outcome was 24.2% (95% CI 15.9-33.5%; n = 22) in the LMWH group and 18.5% (8.5-31.5%; n = 8) in the DOAC group (HR 1.51 [0.695-3.297]). Two recurrent VTE occurred (both in the DOAC group while off-treatment). Nine (9.4%) LMWH-treated patients had major bleeding compared to 1 (2.1%) DOAC-treated patient (HR 4.85 [0.64-36.56]). This study generates the hypothesis that DOACs may be a safe and effective alternative to LMWH for VTE in patients with HM types represented in the study.

Predicting outcomes of hematological malignancy patients admitted to critical care

BackgroundCritical care (CC) admission has traditionally been viewed as likely to result in a poor outcome for hematological malignancy (HM) patients. Such a view can have implications for decisions surrounding CC admission. Recent studies have challenged this poor prognostication, however, there still remains limited data to support CC admission and escalation decisions and to elucidate risk factors which independently predict short- and longer-term survival outcomes.MethodsWe retrospectively analyzed a large cohort of adult HM patients (n=437) admitted to CC over a sixteen-year period, with the specific aim of identifying risk factors present at CC unit admission that could help to predict outcome. We assessed all-cause mortality at CC discharge (CC mortality, primary outcome) and at further time points (hospital discharge and 12-months post-discharge from CC). Single variable and multivariate analyses were performed to identify independent predictors of outcome.ResultsCC unit and hospital mortality rates were 33.4% (146 patients) and 46.2% (202 patients) respectively. At six-month and one-year follow-up, mortality increased to 59.5% and 67.9% respectively. At single variable adjusted regression analysis, eight factors were associated with CC mortality: APACHE II score, the number of organs supported, requirement for continuous renal replacement therapy (CRRT), cardiovascular support, or respiratory support (invasive and non-invasive), the ratio between arterial partial pressure of oxygen (PaO2) and the inspired oxygen concentration (FiO2) (P/F ratio) on CC admission, and the lowest P/F ratio during CC admission. However, only three factors showed independent predictive capacity for CC outcome at multivariate logistic regression analysis; APACHE II score on admission, requirement for ventilation and lowest P/F ratio.ConclusionOne third of HM patients admitted to CC died on the unit and, following admission to CC, approximately one-third of HM patients survived over 1 year. Our data show that, while a diagnosis of HM should not preclude admission of patients who might otherwise benefit from CC support, the prognosis of those with a high APACHE II score upon admission, or those requiring IMV remains poor, despite considerable advances in IMV techniques.

High-titer post-vaccine COVID-19 convalescent plasma for immunocompromised patients during the first omicron surge.

Transplant and hematologic malignancy patients have high Coronavirus disease 2019 (COVID-19) mortality and impaired vaccination responses. Omicron variant evades several monoclonal antibodies previously used in immunocompromised patients. Polyclonal COVID-19 convalescent plasma (CCP) may provide broader neutralizing capacity against new variants at high titers. Vaccination increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer in convalescent donors. We conducted a retrospective chart review of hospitalized immunocompromised patients with COVID-19 who received high-titer CCP during the first omicron surge, collected from vaccinated donors within 6 months of pre-omicron COVID-19. Data on safety and outcomes were extracted. A total of 44 immunocompromised patients were included, 59.1% with solid organ transplant, 22.7% with hematopoietic cell transplant, 11.4% with hematologic malignancy, and 6.8% with autoimmune disease. Overall, 95% of CCP units transfused were from recently recovered and vaccinated donors and had SARS-CoV-2 antibody results 8- to 37-fold higher than the Food and Drug Administration's cutoff for high-titer CCP. There were two mild transfusion reactions. A total of 30-day mortality was 4.5%. There were no differences in 100-day mortality by underlying diagnosis, levels of immunosuppression, and timing of CCP administration. Patients with higher immunosuppression had significantly higher mean World Health Organization clinical progression scores at 30-day post-CCP compared to those with lower immunosuppression. CCP is a safe, globally available treatment for immunocompromised patients with COVID-19. Mortality was lower in our cohort than that of COVID-19 patients with similar immunocompromising conditions. Post-vaccine CCP with very high titers should be prioritized for study in immunocompromised patients. Post-vaccine CCP has the potential to keep pace with new variants by overcoming mutations at sufficiently high titer.